If you’re looking to get into the sterile injectables business or gain an understanding of how sterile injectables are produced, this is just the article for you.
What are sterile injectables?
Before we talk about sterile injectables, we want to talk about sterility. What is sterility? Sterility is defined as the absence of bacteria or other microorganisms. When sterile manufacturing injectables, a specimen would be considered sterile only when it is absolutely and completely free of viable microorganisms.
Now coming to injectables. Parenterals are pharma preparations which are administered any way other than orally. Injectables are a kind of parenteral. They allow a more speedy delivery of drugs into target tissues or the bloodstream as opposed to oral drugs which need to make their way through the alimentary canal first. Sterile injection vials, ampoules and pre-filled syringes are all different ways of packaging such drugs which may differ based on the characteristics of the drug, the desired speed on onset, and the route of administration.
Because they are administered directly to the target tissues, injectables get absorbed fairly quickly and are completely bioavailable. But for the same reasons, there is no way around sterile manufacturing injectables. Drugs administered orally also have stringent manufacturing and handling processes, but if there are some bacteria there, there is a high chance they will be eliminated by the digestive system. Injectables, however, bypass many of the body’s natural defences against pathogens. This means that all injectables must be sterile.
There are a few different methods to administer sterile injectables. Subcutaneous injections, like insulin, are injected into the fat tissue between skin and muscle. Intramuscular and intravenous injectables have fairly self-explanatory names – they are administered into muscles (like flu shots) and veins, respectively. Intraperitoneal, intraosseous, intracardiac, and intraarticular injections are other administration methods, but their use is a lot rarer than the first three we’ve mentioned here.
Challenges in sterile manufacturing injectables
Considering that there is absolutely no scope for contamination when producing SVPs and LVPs, naturally, producing them has its fair share of challenges with aseptic practices. When we discuss how sterile injection vials, ampoules etc are produced, we will see just how complex the process can be. Any lapses in the process can have catastrophic effects on the health of patients who use affected injectables. Not to mention the drug recalls, plant shutdowns or other consequences of injectables failing sterility tests which can ultimately lead to drug shortages, as has already happened in the past.
Guidance for sterile manufacturing injectables
Producing sterile injectables is a complex process, but luckily, there are guidelines out there to support you in your planning and decision-making. For instance, the US FDA has issued guidance in the form of current Good Manufacturing Practice for sterile drug products produced by aseptic processing. These guidelines help manufacturers meet regulatory requirements by paying attention to possible sources of contamination like air, water, equipment, personnel and drug components and finding ways to build quality into the facility design and production process. The WHO also has GMP for sterile pharmaceutical products which will help you understand and control for all possible variables in the sterile injectable manufacturing process.
Sterile injectable production process
Manufacturing sterile injection vials, syringes and ampoules is all highly regulated. The process involves dedicated clean areas, highly trained personnel, and specifically handled equipment to get the job done. There are two ways to produce sterile injectables: aseptic manufacturing and terminal sterilisation. Depending on the method you need to employ, you will need a process partner who will help you with complete plant design – from storage and manufacturing to the last point of filling, packaging and labelling.
When it comes to manufacturing and compounding vessels, you need facilities to use water for injection as a solvent for APIs. Here, different ingredients that make up your final drug are mixed under specific temperature, pressure and pH conditions. Oxygen is voided through nitrogen sparging to prevent the growth or activity of microbes. The prepared product is sampled and tested for quality before it is moved from a manufacturing vessel to a holding vessel after being passed through sterile filters or a pump.
Holding or storage vessels also have their share of process requirements. They must be placed in grade B areas under positive nitrogen pressure. The vessel must be sterilised and filled with pure steam when it is still empty.
Terminal sterilisation vs. aseptic manufacturing
In terminal sterilization, the focus is on a sterile end-product, even though every step of the manufacturing process may not be completely sterile. There are definitely strict standards to follow to reduce the risk of contamination, but the actual sterilisation happens at the very end of the process, so standards aren’t as strict as in aseptic manufacturing.
After a parenteral is produced, it is filled into the final container it will be in and sealed. After this, the product – the drug, and the vial or ampoule – are sterilised together, killing any pathogens that may have made their way into the product. Terminal sterilization may be carried out using dry or moist heat, radiation like gamma rays, or gases like ethylene oxide.
Sterile injectables made sterile using this method cost less to produce because the process is less specialised. But not all drugs are stable when subjected to heat or radiation for sterilization. In such cases, manufacturers must rely on aseptic manufacturing.
In aseptic manufacturing, every process – from start to finish – is carefully controlled to remove the possibility of contamination. There is no final sterilisation as in the process mentioned above, so each component – like process vessels, vials, ampoules, equipment, excipients, APIs – must be sterilised or put through relevant processes separately to eliminate microbial activity. While the drugs themselves cannot be sterilised, all the other equipment, containers and packaging can individually use the same methods as terminal sterilisation to rid them of microbial contamination.
Aseptic manufacturing usually happens in a cleanroom, where even personnel are completely suited up in protective gear so that they don’t shed pathogens. Further, testing is performed at various stages of the process to make sure the end product is actually pyrogen- and endotoxin-free.
Quality control
Sterility testing is essentially a destructive process. This means that by virtue of extracting a sample and putting it through tests, its sterility is lost – that sample cannot be administered to a patient. So first, quality control in sterile manufacturing injectables is built into the process. Second, the testing that does happen at the end involves examining only a few samples which are chosen to be as representative of the entire batch as possible. This isn’t a 100% foolproof method, but it is the only way the quality of the product can be guessed at without destroying the entire batch. Further, validation of the sterilization cycle for terminally sterilised products and media simulation for aseptically produced drugs also help assure quality.
Ultimately, if all of these processes are not carried out with great attention to detail – if poor quality excipients or APIs are used, if processes don’t account for sterility well enough, or if packaging design leads to the introduction of contaminants – injectables can lead to terrible consequences for the people who use them.
This is precisely why you need a process and high purity partner who is skilled and experienced in manufacturing equipment for sterile injectables. TSA has nearly 20 years of experience delivering superlative equipment in over 500 projects in India and overseas. Our customer first approach and are unwillingness to back down from any challenge make us the perfect partner for your process and high purity problems. Reach out to us for a chat today.
